therapy of infections due to carbapenem-resistant …...the prevalence of carbapenem-resistant...

Infection & Chemotherapyhttp://dx.doi.org/10.3947/ic.2014.46.3.149

Infect Chemother 2014;46(3):149-164

pISSN 2093-2340 · eISSN 2092-6448

Received: August 11, 2014Corresponding Author : Yohei Doi Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, S829 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USATel: +1-412-648-9445, Fax: +1-412-648-8521 Email: [email protected]

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Therapy of Infections due to Carbapenem-Resistant Gram-Negative PathogensChang-Seop Lee1,2, and Yohei Doi11Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; 2Department of Internal Medicine and Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea

The prevalence of carbapenem-resistant gram-negative bacterial pathogens (CRGNs) has increased dramatically during the last 10 years, but the optimal treatment for CRGN infections is not well established due to the relative scarcity of robust clinical data. The polymyxins remain the most consistently active agents against CRGNs in vitro. Tigecycline, based on its in vitro anti-bacterial spectrum, could also be considered as a therapeutic option in the treatment of infections caused by certain CRGNs. Other agents, including aminoglycosides, rifampin, trimethoprim-sulfamethoxazole, fosfomycin and fluoroquinolones, could be considered as monotherapy or combination therapy against CRGNs in appropriate contexts, as combination therapy with two or more in vitro active drugs appears to be more effective than monotherapy based on some clinical data. Several promising new agents are in late-stage clinical development, including ceftolozane-tazobactam, ceftazidime-avibactam and plazomicin. Given the shortage of adequate treatment options, containment of CRGNs should be pursued through implementation of ade-quate infection prevention procedures and antimicrobial stewardship to reduce the disease burden and prevent future outbreaks of CRGNs.

Key Words: Combination drug therapy; Polymyxins; Colistin; Tigecycline; Carbapenemase

Review Article

Introduction

Carbapenems (ertapenem, imipenem, meropenem, and

doripenem) are often considered the last resort agents re-

served for treatment of infections due to highly antimicrobi-

al-resistant organisms such as Pseudomonas aeruginosa,

Acinetobacter baumannii, and Enterobacteriaceae producing

extended-spectrum β-lactamase (ESBL) or plasmid-mediated

AmpC β-lactamase. However, the prevalence of carbapen-

em-resistant gram-negative pathogens has increased dramati-

cally in the last decade [1]. The most common and clinically

relevant mechanism underlying carbapenem resistance is

production of carbapenem-hydrolyzing β-lactamases, or car-

bapenemeases, which often confer resistance not only to car-

bapenems but to most β-lactam agents. Many factors, such as

antimicrobial use in humans and food animals, international

Lee CS, et al. • Treatment of carbapenem-resistant gram-negative bacteria www.icjournal.org150

travel, migration, and importation of food products, contrib-

ute to the emergence and spread of these organisms far be-

yond their countries of origin. The current and extensive

spread of carbapenem-resistant gram-negative pathogens is a

cause for concern since they are also frequently resistant to

non-β-lactam agents, therefore presenting with multidrug re-

sistance (MDR), or even extensive drug resistance (XDR).

The aim of this review is to summarize treatment consider-

ations for six representative gram-negative pathogens which

clinicians commonly encounter in hospitals in the context of

carbapenem resistance: 1) Acinetobacter baumannii, 2) Pseu-

domonas aeruginosa, 3) Klebsiella pneumoniae, 4) Esche-

richia coli, 5) Enterobacter spp., and 6) Stenotrophomonas

maltophilia. We will focus our discussion on the management

of infections caused by carbapenem-resistant strains, and also

MDR and XDR strains as appropriate.

Classification of carbapenemases

Carbapenemases are the β-lactamases with the widest spec-

trum of activity in general (Table 1). In addition to carbapen-

ems, carbapenemases also hydrolyze most other members of

the β-lactam family with a few exceptions. On the basis of

their molecular structure, carbapenemases are classified into

Ambler’s class A, B, or D enzymes [2]. The plasmid-borne,

class A Klebsiella pneumoniae carbapenemases (KPCs) are

currently the most prevalent and widely distributed carbap-

enemases [3]. Detection of KPC-producing organisms in mi-

crobiology laboratories is not always straightforward because

some isolates display minimum inhibitory concentrations

(MICs) against imipenem or meropenem that remain in the

susceptible range. In vitro studies have suggested that ertape-

nem is the most sensitive carbapenem substrate for detection

of KPC production [4]. Other clinically important carbapene-

mases include the class B metallo-β-lactamases (MBLs; e.g.,

NDMs, IMPs, VIMs) and the class D OXA-type carbapenemas-

es (e.g., OXA-23 in A. baumannii and OXA-48 in K. pneumoni-

ae). The latter group is unique in that they hydrolyze penicillins

and carbapenems but not cephalosporins. These carbapene-

mase genes are borne on plasmids, which can facilitate their in-

tra- and interspecies dissemination. Besides carbapenemase

production, these organisms may exhibit additional carbapen-

em resistance mechanisms, such as augmentation of efflux

pumps and porin loss that can further elevate carbapenem

MICs [5].

Treatment options for infections due to carbapenem-resistant gram-negative pathogens

1. Acinetobacter baumanniiA. baumannii has become a major healthcare-associated

pathogen worldwide in the last two decades [6]. The common

and challenging presentations include ventilator-associated

pneumonia, bacteremia, and wound infection. Mortality from

invasive A. baumannii infection is high for carbapenem-resis-

tant isolates, with crude mortality ranging from 16 to 76%,

which is higher than the mortality of 5 to 53% from infections

with carbapenem-susceptible isolates [7]. In the treatment of

carbapenem-resistant A. baumannii infection, colistin, tige-

cycline and sulbactam (as part of ampicillin-sulbactam or ce-

Table 1. Classification of carbapenemases

Class Subclass Examples Substrates other than carbapenemsInhibition by clavulanate

A NMC-A Cephamycins Yes

IMI-1, IMI-2 All β-lactams

SME-1, SME-2, SME-3 Penicillins, aztreonam

KPC-2, KPC-3 All β-lactams

GES-2, GES-4, GES-5, GES-6P enicillins, expanded-spectrum cephalosporins, azt-

reonam (variable)

B B1 NDM, IMP, VIM, GIM, SPM, CcrA All β-lactams except aztreonam No

B2 CphA None

B3 L1, FEZ-1, GOB-1, CAU-1 P enicillins, expanded-spectrum cephalosporins (variable)

D O XA-23, OXA-40, OXA-48, OXA-50, OXA-51, OXA-55, OXA-58, OXA-60, OXA-62

Penicillins including oxacillin Variable

http://dx.doi.org/10.3947/ic.2014.46.3.149 • Infect Chemother 2014;46(3):149-164www.icjournal.org 151

foperazone-sulbactam) are often used alone or in various

combinations.

1) Colistin

Polymyxins (colistin and polymyxin B) exert their bacteri-

cidal activity through interactions with lipid A on the outer

membrane and are active against most gram-negative species

with a few exceptions (e.g. Serratia marcescens, Proteus spp.,

Providencia spp.) Between colistin and polymyxin B, colistin

is used more extensively worldwide due to its better availabili-

ty. Among Acinetobacter clinical isolates collected from hos-

pitals in the United States in 2010, 94.7% were susceptible to

colistin [8]. Clinical data on the efficacy of colistin in the treat-

ment of carbapenem-resistant A. baumannii infections are

mostly observational, but data from several prospective, ran-

domized studies addressing the efficacy of colistin-based

combination therapy are also emerging.

Colistin maintains excellent activity against A. baumannii,

but whether treatment of invasive infection due to A. bau-

mannii with this agent alone is adequate has not been defini-

tively established. In a retrospective study of patients with

ventilator-associated pneumonia caused by A. baumannii

who were treated according to susceptibility of the organism

with colistin or imipenem, clinical cure and in-hospital mor-

tality rates were comparable at 57% each and 61.9% and

64.2%, respectively, suggesting that colistin might be a reason-

able alternative for imipenem [9]. On the other hand, in an-

other study of invasive infections caused by carbapenem-re-

sistant A. baumannii and treated with a polymyxin or

ampicillin-sulbactam, therapy with a polymyxin was an inde-

pendent risk factor for in-hospital mortality (odds ratio [OR]:

2.07, P = 0.041), but the medial daily dose of colistin was quite

low compared with today’s standards [10]. Overall, the limited

data suggest that colistin likely has clinical efficacy compara-

ble with carbapenem for invasive A. baumannii infection

when an adequate dose is used [11].

Nebulized colistin is increasingly utilized in the manage-

ment of acute A. baumannii infection, with or without intra-

venous colistin. In a case-control study conducted in Taiwan,

patients with respiratory secretions growing MDR A. bau-

mannii eradicated the organism sooner when they were given

nebulized colistin, with or without intravenous colistin, com-

pared with when no nebulized colistin therapy was given (8.2

days and 21.5 days; P < 0.001) [12]. However, there were no

differences in the in-hospital mortality. In a randomized,

open-label trial of 100 patients with MDR gram-negative

pathogens including A. baumannii conducted in Thailand, fa-

vorable microbiological outcome was achieved significantly

more frequently among those receiving both nebulized and

intravenous colistin (60.9%) than among those receiving in-

travenous colistin only (38.2%; P = 0.03), but there was no dif-

ference in the rates of favorable clinical outcome in this study,

either [13]. Nebulized colistin may therefore expedite micro-

biological eradication in the airways but has not been associ-

ated with clinical benefit.

2) Sulbactam

Sulbactam is a β-lactamase inhibitor which also has intrin-

sic activity against Acinetobacter spp. including A. bauman-

nii. Ampicillin-sulbactam susceptibility of 63.6% has been re-

ported for Acinetobacter spp. isolates collected from U.S.

hospitals in the early 2000s [14]. However, the susceptibility

rate declined from 89% in 2003 to 40% in 2008 in one hospital

system in the U.S. along with increased use of this agent [15].

Carbapenemases produced by A. baumannii, such as OXA-

23, do not affect sulbactam. Therefore, some carbapenem-re-

sistant strains remain susceptible to sulbactam, making it a

potentially useful alternative.

A head-to-head comparison of ampicillin-sulbactam and

colistin was made in a small randomized study, where 28 pa-

tients with ventilator-associated pneumonia due to XDR A.

baumannii received either ampicillin-sulbactam (9 g of sul-

bactam/day) or colistin (270 mg colistin base activity [CBA]/

day) [16]. The clinical response rates, bacteriological success

rates, 14- and 28-day mortality rates and the rates of adverse

events were all comparable between the two groups. These

limited data suggest that sulbactam-containing regimens may

have a role in the treatment of infections caused by carbapen-

em-resistant A. baumannii that remain susceptible to sulbac-

tam.

3) Tigecycline

Tigecycline is a glycylcycline derivative of minocycline

which was designed to circumvent common tetracycline re-

sistance mechanisms. It has unique pharmacokinetics with a

large volume of distribution resulting in low serum peak con-

centration of 0.7 to 0.8 μg/mL after the standard loading dose

of 100 mg [17]. The use of tigecycline for bacteremia is contro-

versial for this reason. An infection-related mortality of 56%

has been reported for patients with carbapenem-resistant A.

baumannii bloodstream infection who were treated with tige-

cycline despite in vitro susceptibility in a small series [18]. In a

larger case series on the use of tigecycline for XDR A. bau-

mannii infections, 266 patients were treated with tigecycline


alone or in combination with another agent (a carbapenem,

expanded-spectrum cephalosporin or piperacillin-tazobact-

am), and 120 were treated with imipenem and sulbactam [19].

The patients who received tigecycline were less ill, evidenced

by significantly lower rates of intensive care unit stay, febrile

illness, abnormal serum creatinine and sepsis. There was no

difference in 30-day mortality between the two groups, and a

lower percentage of patients experienced unfavorable clinical

outcome in the tigecycline group (30.8% and 50.0%; P < 0.001).

On the other hand, in a series of 9 patients who received tige-

cycline for bacteremia due to tigecycline-susceptible, carbap-

enem-resistant A. baumannii, 5 (56%) deaths were related to

bacteremia and 1 breakthrough carbapenem-resistant Acine-

tobacter baumannii bacteremia case was observed during

therapy with tigecycline [18]. It has been suggested in a ran-

domized study of hospital-acquired pneumonia that a higher

dose of tigecycline (a loading dose of 200 mg followed by 100

mg instead of the approved 50 mg twice a day) may improve

the clinical response rate without increasing adverse events,

but there were too few patients with A. baumannii pneumo-

nia in this study to draw definitive conclusions [20]. Overall,

tigecycline may have a role in the definitive therapy of carbap-

enem-resistant A. baumannii infections when the patients

are not severely ill, but it should probably be avoided for criti-

cally ill patients, at least as monotherapy.

4) Minocycline

Minocycline, like tigecycline, inhibits the 30S ribosomal

subunits. It is more active against A. baumannii than doxycy-

cline which is prone to efflux-mediated resistance. In a sur-

veillance study of MDR A. baumannii isolates collected in the

U.S., 72.1% were susceptible to minocycline despite a very low

susceptibility rate to carbapenems (8.7%) [21]. Clinical data

on the use of this agent are scarce. In a series of 8 military pa-

tients treated with oral minocycline for traumatic wound in-

fections due to MDR A. baumannii, minocycline therapy re-

sulted in clinical cure in 7 of the patients [22]. In another small

series, 4 patients with ventilator-associated pneumonia due to

XDR A. baumannii were treated with intravenous minocy-

cline [23]. All 4 patients had clinical improvement, and 3 of

them had microbiologic clearance as well. While clinical data

are lacking, the compelling in vitro activity suggests that mi-

nocycline should be studied further in the context of de-esca-

lation therapy given the availability of oral formulations.

5) Rifampin

Rifampin by itself is not considered for treatment of A. bau-

mannii infection due to rapid emergence of resistance, but its

potential role as an adjunct to other active agents has been ex-

plored. In an open-label, randomized trial comparing the effi-

cacy of colistin and colistin plus rifampin for ventilator-associ-

ated pneumonia due to carbapenem-resistant A. baumannii,

22 patients were treated with colistin alone, and 21 patients

were treated with the combination [24]. The baseline patient

characteristics were largely comparable. The crude in-hospital

mortality and pneumonia-related mortality were higher for

the colistin group (72.7% and 63.6%) compared with the com-

bination group (61.9% and 38.1%), though the differences did

not reach statistical significance. No hepatotoxicity from ri-

fampin was observed. Another study was conducted in Italy

as a multicenter, open-label, randomized trial comparing the

efficacy of colistin and colistin plus rifampin [25]. A total of

210 patients with life-threatening infection due to XDR, colis-

tin-susceptible A. baumannii were enrolled. The baseline

characteristics were again comparable between the groups.

There was no mortality difference between the two groups

(43.4% for the combination group, 42.9% for the colistin

group), although the microbiologic eradication rate was sig-

nificantly higher in the combination group (60.6% and 44.8%;

P = 0.034). Hepatic dysfunction was more common in the

combination group, but the difference was not statistically sig-

nificant (20.8% and 11.9%; P = 0.13). These data suggest that

the addition of rifampin to colistin may facilitate microbiolog-

ical clearance of A. baumannii but is unlikely to convey clini-

cal benefit in terms of improved patient survival.

6) Fosfomycin

Fosfomycin is not active against A. baumannii, but in vitro

synergy has been reported between fosfomycin and colistin or

sulbactam [26], and a pilot randomized controlled trial has

been conducted comparing the efficacy of colistin and colistin

plus fosfomycin for infections caused by carbapenem-resis-

tant A. baumannii [27]. In this study of 94 patients, fosfomy-

cin was given at 4 g every 12 hours intravenously, and therapy

was given for 7 to 14 days. The two groups did not differ in fa-

vorable clinical outcomes (59.6% and 55.3%) or mortality at 28

days (46.8% and 57.4%), whereas microbiological eradication

rates were significantly higher in the combination group

(100% and 81.2%; P = 0.01). The small size of the study pre-

cludes definitive conclusions, and dosing of fosfomycin was

relatively conservative. Nonetheless, this combination may

merit further investigation given the trend for lower mortality

in the combination group coupled with the favorable safety

profile of fosfomycin.


7) Other combination therapy

In an observational study of 250 XDR A. baumannii blood-

stream infections, 36 patients received colistin monotherapy

and 214 patients received colistin-based combination thera-

py, including 102 with a carbapenem, 69 with ampicillin-sul-

bactam or sulbactam, and 43 with other agents [28]. The base-

line characteristics were comparable among the 4 groups, and

all isolates were susceptible to colistin. The in-hospital mortal-

ity rate was significantly lower in the colistin-based combina-

tion groups compared to the colistin monotherapy group (52.3

% and 72.2 %; P = 0.03), and the rate of microbiological eradi-

cation was significantly higher in the combination groups

than the monotherapy group (79.9 % and 55.6 %; P = 0.001). In

another observational study of 69 patients with solid organ

transplantation who developed XDR A. baumannii infection,

treatment with a combination of colistin and a carbapenem

was an independent predictor of survival [29]. While these

data are limited by the observational and retrospective nature

of the studies they are derived from, they overall support the

use of colistin-containing combination regimens for the treat-

ment of invasive carbapenem-resistant and XDR A. bauman-

nii infections.

8) New agents under development

Eravacycline is a novel fluorocycline with activity against

gram-positive and gram-negative pathogens in vitro, includ-

ing A. baumannii. Among 52 A. baumannii isolates display-

ing resistance to carbapenems, fluoroquinolones, and amino-

glycosides, MIC50/90 values of eravacycline were 0.5/2 μg/mL

[30]. A phase 2, randomized, double-blind study was conduct-

ed to evaluate the efficacy and safety of eravacycline in com-

parison with ertapenem in patients with complicated in-

tra-abdominal infections [31]. The clinical success rates were

92.9% to 100% for those receiving eravacycline and 92.3% for

those receiving ertapenem, respectively. The adverse event

rates were 28.6% to 35.8% and 26.7%, respectively. The study

however did not include infections due to A. baumannii.

2. Pseudomonas aeruginosaP. aeruginosa is found in various environmental sources but

also causes serious hospital-acquired infections. Like A. bau-

mannii, it has the ability to develop resistance to multiple

classes of antimicrobial agents which often includes carbap-

enems. The common types of infections include health-

care-associated pneumonia, bloodstream infection and uri-

nary tract infection. P. aeruginosa is also a major pathogen

that colonizes the airways of cystic fibrosis patients and caus-

es repeated exacerbations with progressive development of

multidrug resistance.

1) Colistin

Studies have shown that, despite the risk for nephrotoxicity

in patients receiving colistin, colistin may be useful for salvage

therapy of P. aeruginosa infection when therapeutic choices

are severely limited due to resistance to commonly used

agents, including carbapenems. A recent survey in the U.S. in-

dicated 98.8% susceptibility of P. aeruginosa to this agent [32].

In a retrospective cohort study where colistin use in 23 criti-

cally ill patients with MDR P. aeruginosa infection was exam-

ined, favorable clinical response was observed in 14 patients

(61%), with only 3 patients experiencing relapse of infection.

Bacteremia was the only significant factor associated with

treatment failure (P = 0.02) [33]. In another retrospective anal-

ysis of 258 episodes of MDR gram-negative infections, which

included 68 cases caused by P. aeruginosa, higher daily doses

of colistin were independently associated with better survival

regardless of the pathogen [34]. Finally, in a retrospective co-

hort study of 95 cancer patients with MDR P. aeruginosa in-

fections who were treated with either colistin or another an-

ti-pseudomonal agent, a significantly higher clinical response

rate was observed among patients who received colistin (P =

0.026) [35]. Although randomized studies are lacking, these

data suggest that colistin is likely a viable alternative for the

therapy of P. aeruginosa infections when other anti-pseudo-

monal agents are inactive or treatment with them has failed.

Nebulized colistin has been used in patients with P. aerugi-

nosa respiratory tract infection, particularly in the setting of

cystic fibrosis. This mode of delivery is used to achieve high

drug levels in the respiratory tract while minimizing systemic

adverse effects. In one retrospective cohort study, nebulized

colistin was used alone in the treatment of 21 patients with

pneumonia due to MDR A. baumannii or P. aeruginosa [36].

The overall clinical and microbiological response rates were

57% and 86%, respectively, and nephrotoxicity was not ob-

served. Another prospective observational study compared

the efficacy of nebulized colistin for 14 days plus 3 days of in-

travenous aminoglycoside for ventilator-associated pneumo-

nia due to MDR P. aeruginosa or A. baumannii and 14 days of

intravenous β-lactam therapy plus 3 days of intravenous ami-

noglycoside or fluoroquinolone for the same condition due to

susceptible P. aeruginosa or A. baumannii [37]. In this study,

67% of those treated with nebulized colistin were clinically

cured at the end of treatment compared with 66% treated with

intravenous β-lactams, suggesting that nebulized colistin with


a short course of intravenous aminoglycoside may be as effi-

cacious as β-lactam-based intravenous therapy. These data

suggest that nebulized colistin may be a useful adjunct to in-

travenous therapy in the treatment of P. aeruginosa, but

whether it can be used alone in the management of pneumo-

nia remains to be seen.

2) Fosfomycin

MICs of fosfomycin for P. aeruginosa cluster around 64 μg/

mL, and its role in the management of carbapenem-resistant

P. aeruginosa infections has been explored. In a series of 8

hospitalized patients with a urine culture growing carbapen-

em-resistant P. aeruginosa who were treated with fosfomycin,

the microbiological cure rate was 38% after receiving an average

of 2.9 fosfomycin doses per treatment course [38]. In a cohort

study examining the outcome of 30 patients with P. aeruginosa

infection treated with fosfomycin, 86.7% had favorable clinical

outcomes [39]. In another observational case series, the out-

comes of critically ill patients treated with fosfomycin for infec-

tions due to XDR, carbapenemase-producing gram-negative

bacteria were examined [40]. Among the 17 patients with P.

aeruginosa infection, the clinical success rate was 83.3% and

the microbiological success rate was 66.7% at day 14. Finally, a

recent retrospective study compared the outcomes of patients

with hospital-acquired and ventilator-associated bacterial

pneumonia due to P. aeruginosa with intermediate resistance

to carbapenems who were treated with doripenem and fosfo-

mycin or colistin and fosfomycin [41]. No differences were de-

tected between the groups regarding clinical cure rates (60%

and 58%), microbiological eradication rates (72% and 63%)

and all-cause mortality (40% and 42%). These studies, while

informative, did not address the specific clinical efficacy of

fosfomycin in P. aeruginosa infections since an overwhelming

majority received additional agents. A prospective study

where patients would receive standard therapy with or with-

out fosfomycin would be required to answer this question.


Among the agents in late-stage clinical development,

ceftolozane-tazobactam (formerly CXA-201) is undergoing

phase 3 studies for complicated urinary tract infection and

complicated intra-abdominal infection. Ceftolozane is a novel

anti-pseudomonal cephalosporin. This combination is active

against P. aeruginosa, including many isolates that are resistant

to carbapenems [42]. Ceftazidime-avibactam is also in phase 3

studies for the same indications. Avibactam (formerly NXL104)

is a β-lactamase inhibitor which restores the activity of ceftazi-

dime against class A, C, and some class D β-lactamase-produc-

ing gram-negative bacteria [43]. Ceftazidime-avibactam is ac-

tive against some P. aeruginosa isolates that are resistant to

carbapenems. However, it is not active against isolates produc-

ing MBL.

3. Klebsiella pneumoniae The emergence and spread of carbapenem-resistant En-

terobacteriaceae (CRE) is one of the most recent and worri-

some developments in antimicrobial resistance. The problem

is most acute with K. pneumoniae. In the U.S., 8 to 13% of K.

pneumoniae causing hospital-acquired infections are now re-

sistant to carbapenems [44]. While resistance to carbapenems

Table 2. Selected antimicrobial susceptibility for agents with consistent in vitro activity against carbapenemase-producing K. pneumoniae

Antibiotics

Susceptible (%)

Bratu et al. [4] (n=62)

Bratu et al. [45] (n=96)

Castanheira et al. [46] (n=60)a

Satlin et al. [47] (n=16)b

Pena et al. [48] (n=79)

Tigecycline NT 100 100 65 73.4

Tetracycline 32a 66a 66.7 NT NT

Polymyxin B 73 91 93 80 77.2

Gentamicin 65 61 58.3 30 63.3

Amikacin 6 45 53.3 60 77.2

Piperacillin-tazobactam 0.0 0.0 0.0 0 NT

Cefotetan 15 59 NT NT NT

Ciprofloxacin 0.0 2 14.6 15 7.6

NT, not tested.aIncludes 7 Klebsiella oxytoca.bIncludes 3 Enterobacter cloacae and 1 Escherichia coli ; 2 isolates did not produce a carbapenemase and were resistant to carbapenem due to production of extended-spectrum β-lactamase and outer membrane deficiency.


may involve several combined mechanisms including modifi-

cations to outer membrane permeability and up-regulation of

efflux systems, the recent surge in CRE is mostly mediated by

production of carbapenemases. Among various carbapene-

mases, the most frequently encountered one is KPC, therefore

clinical outcome data are most abundant for KPC-producing

K. pneumoniae. Some data are also available on MBL-produc-

ing K. pneumoniae. Options for treating patients infected with

carbapenem-resistant K. pneumoniae are limited as they are

typically resistant to all β-lactam agents including carbapen-

ems, but some strains remain susceptible to gentamicin, and

most remain susceptible to tigecycline and colistin.

Agents consistently shown to have in vitro activity against

KPC-producing K. pneumoniae include tigecycline (65-100%

susceptible), colistin (73-93%), the aminoglycosides (genta-

micin 30-63%, amikacin 6-77%) and tetracyclines (32-67%)

(Table 2) [4, 45-48].

1) Tigecycline

Tigecycline has been used either alone or in combination

with another agent in a number of patients. In a series of 12

patients infected with MBL-producing K. pneumoniae and

treated with tigecycline alone at the standard dose, the overall

clinical response rate was 75% [49]. In a review of 10 clinical

studies investigating the outcomes of infections due to car-

bapenem-resistant, ESBL-producing or MDR Enterobacteria-

ceae, 69.3% of the 33 reported patients treated with tigecycline

achieved resolution of infection [50]. Uniquely low serum

concentrations of tigecycline warrant caution when using this

agent alone to treat documented or potential bacteremic in-

fections, as discussed in 1.3. Highlighting this concern, a case

with persistent breakthrough bacteremia due to a K. pneumo-

niae isolate producing both MBL and ESBL while on tigecy-

cline therapy has been reported [51]. Furthermore, it is not

recommended for the treatment of urinary tract infections

due to its low urine concentration [52].

2) Colistin

In vitro susceptibility of carbapenemase-producing Entero-

bacteriaceae isolates to colistin ranges between 80 and 100%

worldwide [53]. Colistin is often the only agent against car-

bapenemase-producing Enterobacteriaceae that achieves ad-

equate serum levels exceeding the MICs [54].

In a case series including 17 seriously ill patients, 12 patients

were treated successfully with colistin alone or in combina-

tion with either a carbapenem or an active aminoglycoside

[55]. In an outbreak of KPC-producing K. pneumoniae, infec-

tion was successfully treated in 12 patients with an antimicro-

bial regimen containing colistin either as the only active agent,

or with an aminoglycoside, tigecycline, or carbapenem [56]. In

a prospective observational study of 67 patients with blood-

stream infection caused by MBL-producing K. pneumoniae,

12 received appropriate combination therapy with two active

drugs (carbapenem in combination with either colistin or an

active aminoglycoside), and 37 received appropriate therapy

with one active drug (14 carbapenem, 15 colistin, and 8 an ac-

tive aminoglycoside) [57]. Mortality rates were 8.3% for those

who received combination therapy with two active drugs and

27% for those who received therapy with one active drug, sug-

gesting these combinations, almost half of which included

colistin, may be efficacious. However, the outcome was not

stratified for the use of colistin.

More recently, 127 patients with infections due to carbapen-

em-resistant K. pneumoniae in intensive care units across

Greece were studied, which primarily included central venous

catheter-related bacteraemia and ventilator-associated pneu-

monia [58]. Resistance to colistin, tigecycline, gentamicin and

amikacin was detected in 20%, 33%, 21% and 64% of the iso-

lates, respectively. Fourteen-day mortality rates were as fol-

lows: colistin monotherapy, 23.1%; aminoglycoside mono-

therapy, 22.7%; tigecycline monotherapy, 31.3%; tigecycline

plus aminoglycosides, 18.1%; colistin plus aminoglycosides,

11.7%; colistin plus tigecycline, 44.4%. Mortality from inappro-

priate therapy (i.e., no active agent) was 35.0%. As such, colis-

tin is a key agent in the treatment of carbapenem-resistant K.

pneumoniae, with available clinical data generally favoring

combination therapy over monotherapy in general (see also

3.8.).

3) Aminoglycosides

The use of aminoglycosides for KPC-producing K. pneumo-

niae infections was reviewed earlier by Hirsch and Tam [59].

The aminoglycosides were used, alone or in combination, in a

total of 8 patients with a 75% success rate. They had pneumo-

nia, bacteremia or urinary tract infection and were treated

with gentamicin or amikacin, alone or in combination with ci-

profloxacin or tetracycline. However, the small number of pa-

tients and the heterogeneity of patient conditions and regi-

mens precluded interpretation of the outcome data.

In a study of bloodstream infections due to CRE among pa-

tients with hematologic malignancies, gram-negative antimi-

crobial therapy was initiated in response to fever and/or sep-

sis on the day of blood culture collection in nearly all patients

[47]. Only 2 patients received empirical therapy with an agent


to which the CRE isolate was susceptible in vitro, with both

clearing bacteremia. Three patients died before susceptibility

data were available and never received an active agent.

Among the remaining patients, 10 patients received one active

agent, of which amikacin was most common, and 5 patients

received two active agents. The 7-day, 14-day and in-hospital

mortality rates were 39%, 53% and 56%, respectively. All 10

deaths were CRE-related [47]. The high mortality rates are

likely due to the severity of the underlying illnesses in this

population, but it is also possible that effective monotherapy

with amikacin also contributed to the suboptimal clinical out-

come. Overall, there are not sufficient data to support the use

of aminoglycosides monotherapy for the therapy of carbapen-

em-resistant K. pneumoniae infections.

4) Carbapenem

Carbapenems are rarely used alone for treatment of carbap-

enem-resistant K. pneumoniae infections, but before the car-

bapenem breakpoints were lowered by the Clinical and Labo-

ratory Standards Institute (CLSI) in 2010, some cases that

were reported as susceptible to a carbapenem despite pro-

duction of KPC were treated with carbapenem monotherapy.

The aforementioned review by Hirsch and Tam complied

reports on a total of 19 patients who were treated with a car-

bapenem alone or in combination with another agent due to

the apparent susceptible testing results for carbapenems [59].

Strikingly, only 6 of 15 patients treated with carbapenem

monotherapy had clinical success. While infections from iso-

lates with carbapenem MICs of ≤ 4 μg/mL may be treated with

high-dose carbapenem alone from pharmacokinetic and

pharmacodynamics standpoints [60], the proportion of iso-

lates falling within this range is small, and there is a concern

for inadequate response as changes in the porin function may

further raise the carbapenem MICs [61]. Therefore, the exist-

ing data do not support the use of carbapenem alone for inva-

sive carbapenem-resistant K. pneumoniae infections, but it is

increasingly suggested that it should be part of combination

regimens (also see 3.8.).

5) Fosfomycin

Fosfomycin is active against over 90% of KPC-producing K.

pneumoniae when using the susceptibility breakpoint of 64

μg/mL [62]. In a retrospective study of 13 hospitalized patients

with urine culture growing KPC-producing K. pneumoniae

and treated with oral fosfomycin, patients received an average

of 2.9 fosfomycin doses per treatment course, resulting in a

microbiological cure rate of 46% [38]. In another study, intra-

venous fosfomycin in combination with colistin, gentamicin,

or piperacillin-tazobactam resulted in a promising clinical

success rate (100%) in the treatment of serious infections

caused by carbapenem-resistant K. pneumoniae [63]. In a re-

cent prospective case series, the outcomes of critically ill pa-

tients treated with fosfomycin for infections due to XDR, car-

bapenemase-producing gram-negative bacteria were

examined [40]. Among 23 patients with monomicrobial K.

pneumoniae infection, clinical success rate was 56.5% and

microbial success rate was 65.2%, but most of them appear to

have received fosfomycin in combination with another agent

(colistin for the most part). These data suggest that benefit of

fosfomycin in the treatment of infections caused by carbapen-

em-resistant K. pneumoniae may exist, but only in the context

of combination therapy. It should also be kept in mind that

fosfomycin resistance may emerge during therapy, even when

combination therapy is used [64].

6) Temocillin

Temocillin is a 6-α-methoxy derivative of ticarcillin that is

approved for clinical use in several European countries. It is

relatively resistant to hydrolysis by class A β-lactamases in-

cluding KPC [65]. The MICs of temocillin for KPC-producing

K. pneumoniae ranged between 16 and 64 μg/mL, and pro-

duction of KPC in itself does not influence the temocillin

MICs [66]. The susceptibility breakpoints available from the

British Society for Antimicrobial Chemotherapy (BSAC) are

32 μg/mL for urinary tract infection and 8 μg/mL for systemic

infections. Therefore, while specific clinical data are lacking, it

may have a role in the treatment of urinary tract infection due

to CRE. Although the currently licensed dosage is 2 g intrave-

nously twice daily, 2 g thrice daily regimen is under evaluation

and may justify a higher breakpoint for systemic infections

[65].

7) Extended infusion of β-lactam agents

Since the clinical efficacy of β-lactam agents is pharmacoki-

netically predicted by time above MIC, an extended infusion

or continuous infusion is a potential strategy to overcome

higher carbapenem MICs in carbapenemase-producing gram-

negative bacteria. The advantage of this approach has been

suggested in immunocompetent and neutropenic murine

thigh models [67]. A case of successful treatment of KPC-pro-

ducing K. pneumoniae bacteremia with high-dose continuous

infusion meropenem has been reported [68]. However, no oth-

er clinical data addressing the utility this approach specifically

for the treatment of CRE infections are available at this time.


8) Combination therapy

Studies addressing the clinical outcome of CRE infections

have been reviewed recently by Tzouvelekis et al. [69]. Among

889 patients included in this analysis, 441 received combina-

tion therapy and 346 received monotherapy. The mortality

rates were 27.4% for combination therapy and 38.7% for

monotherapy (P < 0.001). The mortality rates for monotherapy

were 40.1% for carbapenem, 41.1% for tigecycline and 42.8%

for colistin. The mortality rates for combination therapy were

30.7% for carbapenem-sparing combinations and 18.8% for

carbapenem-containing combinations, suggesting that the in-

clusion of a carbapenem in the combination may provide sur-

vival benefit. A large proportion of patients in this analysis

were derived from four studies conducted in the U.S., Greece

and Italy addressing the clinical outcome of carbapene-

mase-producing K. pneumoniae bacteremia, most of which

were due to KPC producing isolates. In the study from the U.S.,

the outcomes of a total of 41 patients with bacteremia were

examined [70]. The overall 28-day crude mortality rate was

39.0% in this cohort. In the multivariate analysis, definitive

therapy with a combination regimen was independently asso-

ciated with survival (odds ratio [OR]: 0.07, P = 0.02). The 28-

day mortality was 13.3% in the combination therapy group

compared with 57.8% in the monotherapy group (P = 0.01).

Despite in vitro susceptibility, patients who received mono-

therapy with colistin, polymyxin B or tigecycline had a high

mortality of 66.7%. In the first study from Greece, a total of 53

patients with bacteremia were identified and included [71].

The overall mortality was 52.8%, and the infection-related

mortality was 20%. Appropriate antimicrobial therapy was ad-

ministered to 35 patients. All 20 patients who received combi-

nation therapy (colistin plus tigecycline or tigecycline with

gentamicin) had favorable clinical outcome. In contrast, 7 of

15 patients given appropriate monotherapy (colistin, tigecy-

cline, gentamicin) died (P = 0.001). The study from Italy exam-

ined the clinical outcomes of 125 patients with bloodstream

infections caused by KPC-producing K. pneumoniae [72]. The

overall 30-day mortality rate was 41.6%. A significantly higher

mortality rate was observed among patients treated with

monotherapy (54.3%) compared with those who received

combined therapy (34.1%; P = 0.02). Mortality rates with the

most frequent combinations were 30% for colistin plus tigecy-

cline and 50% for tigecycline plus gentamicin. Notably, defini-

tive therapy with a triple combination of tigecycline, colistin,

and meropenem was associated with increased survival (OR:

0.11, 95% CI: 0.02 to 0.69, P = 0.01). Finally, the second study

from Greece examined the outcome of 205 patients with bac-

teremia due to carbapenemase-producing K. pneumoniae,

163 of which produced KPC [73]. The rate of resistance to

colistin was high at 25.4%. Of 175 patients who received active

definitive therapy, 103 received combination therapy and 72

received monotherapy. The 28-day mortality rates were 27.2%

and 44.4%, respectively (P = 0.003). Additionally, a low mortal-

ity rate (19.3%) was seen among patients given carbapen-

em-containing combinations, and lower carbapenem MICs

were associated with lower mortality, as in the study from Italy.

These data support the use of combination therapy that in-

cludes colistin and/or tigecycline along with a carbapenem in

the therapy of invasive infections due to carbapenem-resistant

K. pneumoniae. On the other hand, patients may fare well re-

gardless of therapy for non-invasive infections such as un-

complicated urinary tract infection. In a retrospective study

examining the clinical outcome of 21 patients with urinary

tract infection due to carbapenem-resistant K. pneumoniae,

90% of them had clinical success regardless of therapy given,

and the overall 30-day mortality was low at 6% [70]. Therefore,

it is important to stratify cases into invasive (i.e. high mortali-

ty) and non-invasive (low mortality) infections and consider

therapeutic approaches accordingly.


There are several new agents with activity against CRE in

late clinical development that merit mention. Avibactam is a

non-β-lactam β-lactamase inhibitor that is active against

known Ambler class A and C β-lactamases with activity

against some Ambler class D enzymes as well [74]. In vitro,

avibactam inhibits the activity of Ambler class A (including

ESBL and KPC), class C (i.e. AmpC), and some class D (in-

cluding OXA-48) enzymes. It is not active against MBLs (e.g.

NDM, VIM, IMP) due to the absence of the active-site serine

residue in these enzymes, and it does not inhibit OXA-type

carbapenemases produced by A. baumannii [75, 76]. Of note,

avibactam has a potent inhibitory activity against KPC that is

substantially greater than that of clavulanate and tazobactam

[74, 77]. Ceftazidime-avibactam is currently in phase 3 trials

for the treatment of complicated intra-abdominal infections

and complicated urinary tract infections. Once approved, it is

expected to play a role in the empiric monotherapy of invasive

infections suspected to be caused by resistant Enterobacteria-

ceae pathogens, and also potentially as definitive therapy of

KPC-producing Enterobacteriaceae infection.

Plazomicin is a novel aminoglycoside that is designed to re-

sist most clinically relevant aminoglycoside modifying en-

zymes and holds promise for the treatment of infections


caused by CRE, including KPC-producing K. pneumoniae [78].

It is currently undergoing a phase 3 superiority trial targeting

CRE bacteremia and pneumonia, where plazomicin-based regi-

mens will be compared with colistin-based regimens. It is how-

ever not active against many of the NDM-producing isolates due

to the co-production of 16S ribosomal RNA methyltransferase.

4. Escherichia coliCarbapenem resistance in Escherichia coli does not occur

naturally, and acquired resistance is rare in this species [79].

More recently, however, KPC-producing E. coli is increasingly

reported in the literature. Clinical outcome data regarding

carbapenem-resistant E. coli infection are extremely scarce to

date. In one case series in the U.S., a total of 13 patients with

infection due to KPC-producing E. coli were identified. Ten

patients were deemed to have infection due to this organism,

whereas 3 patients were found to be colonized only. They

were treated with a variety of definitive antimicrobial therapy,

which included carbapenems, cefepime, trimethoprim-sulfa-

methoxazole, ciprofloxacin, amikacin, tigecycline, and colisti-

methate, alone or in combination. Of those with infection, 6

were alive and 3 had died by 28 days after infection [80]. The

study was not large enough to correlate specific regimens with

clinical outcome. It is noteworthy that the carbapenem MICs

of carbapenemase-producing E. coli strains are much lower

than those of carbapenemase-producing K. pneumoniae

strains, often falling in the susceptible range for imipenem,

meropenem and doripenem [81, 82]. However, exposure to a

carbapenem has been shown to result in elevated MICs in a

pharmacodynamic model [83]. Therefore, it seems prudent to

avoid the use of carbapenem alone for treatment carbapen-

em-resistant E. coli infection even when the isolate tests sus-

ceptible to a specific carbapenem. Fortunately, they remain

relatively susceptible to non-β-lactam agents such as genta-

micin, amikacin, minocycline and fosfomycin as well as tige-

cycline and colistin [82, 84].

5. Enterobacter spp.Acquired carbapenem resistance is still uncommon among

Enterobacter spp., thus clinical studies of carbapenem-resis-

tant E. cloacae infection are limited in number. In a study of 6

patients infected or colonized with MBL-producing E. cloa-

cae, 4 of 5 patients who had infection died in hospital, 3 of

them before the susceptibility results became available [85].

In another series of 7 patients with carbapenem-resistant E.

cloacae, 2 of which were produced MBL, 3 cases were consid-

ered to represent infection. Two of these 3 patients died by

day 30 [86]. Finally, a series of 11 patients with KPC-producing

Enterobacter spp., including 8 E. cloacae and 3 Enterobacter

aerogenes, was recently published [87]. Six patients had infec-

tion, 2 with bacteremia, 2 with urinary tract infection, and 1

each with meningitis and peritonitis. Two of them did not sur-

vive the hospitalization, including one of the patients with

bacteremia and the patient with meningitis. While they re-

ceived various antimicrobial therapies, the outcome appeared

to be associated with the severity of underlying illness. Inter-

estingly, 2 patients with urinary tract infection had clinical

success with amikacin and fosfomycin or trimethoprim-sulfa-

methoxazole, highlighting that that the type and severity of in-

fection matters when considering clinical outcome.

6. Stenotrophomonas maltophilia S. maltophilia is a gram-negative, non-fermentative bacillus

which is increasingly being recognized as a cause of hospi-

tal-acquired infections. It is inherently resistant to multiple

classes of antibiotics including cephalosporins, carbapenems

and aminoglycosides [88]. Attributable mortality due to inva-

sive S. maltophilia infection has historically ranged around

30% [89, 90], but may increase to 60% among patients who ac-

quire their infection while in the intensive care unit [91]. Tri-

methoprim-sulfamethoxazole (TMP-SMX) is considered the

first-line therapy because of its excellent in vitro activity

against the majority of isolates, whereas fluoroquinolones are

an alternative option for treatment, if the pathogen is shown

to be susceptible to them in vitro. Ticarcillin-clavulanate has

also been proposed as an alternate therapy to TMP-SMX, but

resistance rates to this agent can be significant depending on

the local epidemiology. While in vitro synergy of various com-

binations of agents has been studied extensively [92], the ma-

jority of clinical data available on the therapy of S. maltophilia

infection address monotherapy by an active agent.

With regards to clinical data, for 98 patients with S. malto-

philia infections, mostly in the respiratory tract, who were

treated with either TMP-SMX or a fluoroquinolone alone, the

in-hospital mortality rates were 20% and 25% for those who

received TMP-SXT and fluoroquinolone, respectively, and the

microbiological cure rates were 65% and 62%, respectively

[93]. At least two more retrospective studies evaluating the ef-

ficacy of levofloxacin and TMP-SMX in the treatment of S.

maltophilia bacteremia reported comparable 30-day mortali-

ty rates [94, 95]. In a recent series of 45 patients, the efficacy of

tigecycline treatment in nosocomial S. maltophilia infections

was compared with TMP-SMX [96]. Pneumonia was the most

common cause of infection (51.1%), followed by surgical site


infection, and bacteremia. For therapy, 57.8% received TMP-

SMX and 42.2% received tigecycline within 24 hours after the

culture results. Clinical improvement was observed for 69.2%

in the TMP-SMX group and 68.4% in the tigecycline group on

day 14. The 30-day mortality rates were 30.8% and 21.1% in

the TMP-SMX and tigecycline groups, respectively. This

showed that tigecycline could also be considered an alterna-

tive treatment option against nosocomial S. maltophilia in-

fection.

Conclusion

Carbapenem resistant gram-negative bacteria are spreading

rapidly in the healthcare environments posing a substantial

public health threat worldwide. They primarily affect the

chronically or acutely ill populations, and infections due to

these organisms are generally associated with high mortality.

Despite the scope of the problem, there is a major gap in

knowledge as to how these infections can be managed opti-

mally, with most studies relying on small numbers of patients

and retrospective study designs. However, there are encourag-

ing signs. An increasing number of controlled randomized tri-

als are being conducted and results released to address anti-

microbial therapy, especially for infections due to K.

pneumoniae and A. baumannii, where carbapenem resis-

tance has become endemic in many locales. Nonetheless,

high-quality evidence is still lacking in many scenarios en-

countered in clinical practice. It therefore remains crucial for

clinicians to determine, for each case of carbapenem-resistant

gram-negative bacteria, whether the patient is truly presenting

with infection or merely colonized with the organism, and

carefully consider the therapeutic approach based on the con-

dition of the patient, antimicrobial susceptibility and available

clinical data.

Acknowledgment

The effort of Y.D. was supported in part by research grants

from the National Institutes of Health (R21AI107302 and

R01AI104895).

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